Atomoxetine, known as (R)(−)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine, has the following structure:

Atomoxetine HCl (STRATTERA®) was originally developed as an antidepressant. It is currently marketed for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). Atomoxetine, the (R)-(−) enantiomer of tomoxetine, is an aryloxyphenylpropylamine (e.g., fluoxetine and nisoxetine). It is a competitive inhibitor of norepinephrine uptake in synaptosomes of rat hypothalamus and is approximately 2 and 9 times, respectively, more effective than the racemic mixture and the (+)-enantiomer. See for example: U.S. Pat. No. 4,018,895 (Eli Lilly and Co.), EP 0 052 492 (Eli Lilly and Co.), and EP 0 721 777 (Eli Lilly and Co.).
Several routes of synthesis for 3-aryloxy-3-phenylpropylamines are known in the art. For example, U.S. Pat. No. 4,018,895 by Eli Lilly and Co. discloses an aliphatic nucleophilic displacement of N-protected-3-halogen-3-phenylpropylamines by phenols, followed by N-deprotection. U.S. Pat. No. 4,868,344 by Aldrich-Boranes Inc. relates to the Mitsunobu reaction between 3-hydroxy-3-phenylpropylhalides and phenols, followed by amination of the resulting 3-aryloxy-3-phenylpropylhalides. Unfortunately, the synthetic routes disclosed in these patents require several steps and are burdened by the use of hazardous chemicals, such as diethylazadicarboxylate, triphenylphosphine and thionyl chloride.
U.S. Pat. No. 6,541,668, and WO 00/58262 by Eli Lilly and Co. as well as WO 94/00416 by Richter Gedeon Vegyeszeti Gyar RT disclose an aromatic nucleophilic displacement of an aryl halide by 3-hydroxy-3-phenylpropylamines under strongly basic conditions. The nucleophilic aromatic displacement process disclosed in WO 00/58262 involves reacting N-methyl-3-hydroxy-3-phenylpropylamine with a protected 2-fluorobenzaldehyde, which eventually leads, after functional group interconversion steps, to tomoxetine. The main drawbacks of this process are the additional steps required and the high cost of 2-fluorobenzaldehyde.
U.S. Pat. No. 6,541,668 discloses aromatic nucleophilic displacement conditions in the synthesis of tomoxetine: 1,3-dimethyl-2-imidazolidinone or N-methylpyrrolidinone are used as solvents, starting from N-methyl-3-hydroxy-3-phenylpropylamine and 2-fluorotoluene, under strongly basic conditions (disclosed bases are alkali metal hydrides or alkoxides), at temperatures of less than about 140° C. (yields data are not reported). As pointed out by the '668 patent, aromatic nucleophilic displacement giving tomoxetine cannot be carried out in conditions already known for other 3-aryloxy-3-phenylpropylamines, since 2-fluorotoluene is less activated than other aromatic rings used.
Tomoxetine is an intermediate in the preparation of atomoxetine HCl.
A modest tomoxetine chemical yield with dimethylsulfoxide as a solvent was also reported in Koenig & Mitchell, Tetrahedron Letters, Vol. 35, n. 9, pp. 1339-1342 (1994). The base used is sodium hydride, a more reactive base than alkali metal hydroxides.
Other compounds, such as fluoxetine, can be synthesized through an aromatic nucleophilic displacement process, such as the one disclosed in WO 94/00416.
As indicated by the disadvantages of the methods described in the related art, there is a need in the art therefore for additional processes for preparing tomoxetine in higher yields and shorter reaction times.